Thiazole derivatives for treating dyskinesias caused by a chemical treatment

ABSTRACT

The invention relates to the use of derivatives of thiazoles having general formula (I) for the preparation of a medicament for the treatment or prevention of dyskinesias caused by a chemical treatment. The invention also relates to a combination of thiazole derivatives having general formula (I) and at least one compound selected from among neuroleptics or products that act on the dopaminergic system for the treatment or prevention of dyskinesias caused by a chemical treatment.

CONTINUITY DATA

This application is a national stage application of PCT/FR2006/001638,filed on Jul. 7, 2006, which in turn claims priority to FR 0507303,filed on Jul. 8, 2005; both of which applications are herebyincorporated by reference in their entirety.

BACKGROUND OF INVENTION

1. Field of Invention

A subject of the present invention is thiazole derivatives of generalformula (I) described below for preparing a medicament intended fortreating or preventing dyskinesias caused by a chemical treatment.

2. Description of the Related Art

Dyskinesias are generally characterized by involuntary or abnormalmovement disorders.

Among the dyskinesias, those caused by a chemical treatment aredistinguished. In this case, within the meaning of the presentinvention, the terms induced dyskinesias or tardive dyskinesias areused, these 2 forms of dyskinesias being dyskinesias caused by achemical treatment.

Induced dyskinesias: these are induced by a chemical treatment, such asfor example in patients treated with L-Dopa which is a dopamineprecursor. Patients treated with L-Dopa are generally Parkinsonians,i.e. individuals suffering from Parkinson's disease who present with apathological deficit of Dopamine as the main characteristic of thedisease. Treatment with dopatherapy is absolutely necessary for thesepatients in order to restore a sufficient level of endogenous dopamine.However, in a significant number of patients it causes severe sideeffects which are manifested by so-called induced dyskinesias, generallyafter several years of treatment with L-Dopa. This form of dyskinesiawhich is a serious undesirable iatrogenic effect of L-Dopa results inparticular in the progressive emergence of involuntary movements, musclerigidity and gait disorders. The emergence of this type of dyskinesianever occurs in “de novo” parkinsonian patients having never previouslyreceived treatment with L-Dopa. Unfortunately, at present nosatisfactory treatment exists for dyskinesias induced by Dopatherapy. Aclinician responsible for a parkinsonian suffering from dyskinesiainduced by L-Dopa is then compelled to reduce the daily dose of L-Dopain order to reduce the severity of the abnormal movements (dyskinesia),which is then accompanied by an aggravation of the blockage phenomenadue to Parkinson's disease. The clinician and the patient then have tochoose between 2 evils: blockages or dyskinesia.

At present no satisfactory medicinal treatments exist for dyskinesiasinduced by L-Dopa (a few compounds have been proposed, such as forexample yohimbine, idazoxan or amantadine). Only surgical interventionby stimulation of the globus pallidus constitutes a therapeutic strategywhich could be effective in the most severe cases, which is clearly notsuitable for the majority of patients.

Tardive dyskinesias: these appear tardively in patients receivinglong-term treatment with certain medicaments, in particularneuroleptics. By way of example these are patients suffering fromschizophrenia treated with the typical neurolopetics (such as forexample dopamine D2 receptor agonists) such as haloperidol, or so-calledatypical agonists (dopamine D3 or D4 receptor ligands) such as clozapineor olanzepine. These treatments cause so-called tardive dyskinesias asside-effects. These are in particular abnormal involuntary movements, atthe facial, oral, lingual, masticatory level, and diffuse movements,rhythmic swinging of the trunk, swaying and stamping;

Thus, the therapeutic treatments known at present are not satisfactory.

In order to respond to the needs of patients, it has become necessary tofind a new means for treating these dyskinesias caused by a chemicaltreatment which are very incapacitating for patients.

Therefore the problem that the invention proposes to solve is to providea novel compound suited to treating dyskinesias caused by a chemicaltreatment.

SUMMARY OF THE INVENTION

Unexpectedly, the Applicant has demonstrated that it is possible to usethiazole derivatives of general formula (I) described below forpreparing a medicament intended for treating or preventing dyskinesiascaused by a chemical treatment.

Yet more unexpectedly, the Applicant has demonstrated that thecombination of the thiazole derivatives of general formula (I) describedbelow and at least one compound chosen from the products acting on thedopaminergic system or neuroleptics makes it possible to treat orprevent dyskinesias caused by a chemical treatment.

Finally the use and the combination according to the invention have theadvantage of being able to be utilized in patients and animals sufferingfrom movement disorders.

The combination according to the invention has the advantage of avoidingthe side-effects caused by a long-term therapeutic treatment.

Other advantages and characteristics of the invention will becomeclearly apparent on reading the description and the following exampleswhich are given purely by way of illustration and are in no waylimitative.

DETAILED DESCRIPTION OF THE PREFERRED EMBODIMENTS

A first subject of the invention is the use of a compound of generalformula (I)

in the form of racemic, enantiomeric mixture or any combination of theseforms, in which:

A1 represents a radical (A1)

in which R⁵ represents a hydrogen atom or an alkyl radical, R⁶, R⁷, R⁸represent independently a hydrogen atom or an alkyl, cycloalkyl, hydroxyor alkoxy radical;

B represents a hydrogen atom or an alkyl radical;

n represents an integer from 0 to 5;

R1 and R2 represent independently a hydrogen atom or an alkyl orcycloalkyl radical;

R³ et R⁴ represent independently a hydrogen atom or an alkyl radical, orR³ and R⁴ form together with the nitrogen atom which carries them aheterocycle comprising in total from 1 to 2 heteroatoms and from 5 to 7members, a heterocycle the missing members of which are chosen from—CH₂—, —NR¹⁴—, —O— or —S—, R¹⁴ representing a hydrogen atom or an alkylradical, or a —COR¹⁵, —COOR¹⁵ or —CONR¹⁶R¹⁷ radical, R¹⁵ representing analkyl radical and R¹⁶ and R¹⁷ represent independently a hydrogen atom oran alkyl radical,

or a salt of general formula (I) defined above for preparing amedicament intended for treating or preventing dyskinesias caused by achemical treatment.

Within the meaning of the present invention, by alkyl or alkoxy radicalis meant, unless otherwise specified, a linear or branched alkyl oralkoxy radical containing 1 to 6 carbon atoms. By cycloalkyl radical,unless otherwise specified, is meant a cycloalkyl radical containing 3to 7 carbon atoms.

Preferably, by linear or branched alkyl having 1 to 6 carbon atoms, ismeant in particular the methyl, ethyl, propyl, isopropyl, butyl,isobutyl, sec-butyl and tert-butyl, pentyl, neopentyl, isopentyl, hexyl,isohexyl radicals.

By pharmaceutically acceptable salt is meant in particular within themeaning of the invention addition salts of inorganic acid such ashydrochloride, hydrobromide, hydroiodide, sulphate, phosphate,diphosphate and nitrate or organic acids such as acetate, maleate,fumarate, tartrate, succinate, citrate, lactate, methanesulphonate,p-toluenesulphonate, pamoate and stearate. Also included within thescope of the present invention, when they can be used, are the saltsformed from bases such as sodium or potassium hydroxide. For otherexamples of pharmaceutically acceptable salts, reference can be made to“Salt selection for basic drugs”, Int. J. Pharm. (1986), 33, 201-217.

Moreover, certain of the compounds of general formula (I) can bepresented in the form of enantiomers. The present invention includes thetwo enantiomeric forms and all combinations of these forms, includingthe “R, S” racemic mixtures. In an effort to simplify matters, when nospecific configuration is indicated in the structural formulae, it mustbe understood that the two enantiomeric forms and their mixtures arerepresented.

Preferably, the compounds according to the invention are such that theR⁵ radical of A1 is a hydrogen atom.

Preferably, the compounds according to the invention are such that theR⁶, R⁷, R⁸ radicals of A1 represent independently a hydrogen atom or analkyl radical.

Preferably, the compounds according to the invention are such that n iscomprised between 0 and 3, more preferentially in that n is equal to 0.

More preferentially, the compounds according to the invention are suchthat R¹ represents a hydrogen atom.

Still more preferentially, the compounds according to the invention aresuch that R² represents a hydrogen atom or an alkyl radical.

More particularly, the compounds according to the invention are suchthat R³ or R⁴ represents a hydrogen atom or an alkyl radical.

Still more particularly, the compounds according to the invention aresuch that they are the following compounds:

-   4-[2-(aminomethyl)-1,3-thiazol-4-yl]-2,6-di(tert-butyl)phenol;-   4-{2-[(1R)-1-aminoethyl]-1,3-thiazol-4-yl}-2,6-di-tert-butylphenol-   4-{2-[(1S)-1-aminoethyl]-1,3-thiazol-4-yl}-2,6-di-tert-butylphenol;

Preferably, the purpose of the invention is the use of a compound ofgeneral formula (I) or a salt of general formula (I) defined above forpreparing a medicament intended for treating or preventing dyskinesiascaused by a chemical treatment such as for example induced dyskinesia ortardive dyskinesia.

Preferentially, a subject of the invention is the use of a compound ofgeneral formula (I) or a salt of general formula (I) defined above forpreparing a medicament intended for treating or preventing induceddyskinesias such as for example dyskinesias induced by levodopa(L-Dopa), by the levodopa-benzerazide combination or thelevodopa-carbodopa combination, by pergolide, quinpirole, carbergoline,benzotropine, trihexylphenidyl, ropinorole, pramipexole and any otherdopaminergic derivatives which are substituted for dopamine.

Preferentially, a subject of the invention is the use of a compound ofgeneral formula (I) or a salt of general formula (I) defined above forpreparing a medicament intended for treating or preventing tardivedyskinesias such as for example tardive dyskinesias following treatmentwith phenothiazine derivatives, butyrophenone derivatives, haloperidol,risperidone, tetrabenazine derivatives, clozapine, olanzapine,fluoxetine, buspirone.

The use according to the invention does not relate to the treatment ofdyskinesias not caused by a chemical treatment.

By dyskinesias not caused by a chemical treatment is meant within themeaning of the invention the abnormal pathological movements appearingas a clinical sign of a neurodegenerative disease.

The use according to the invention does not relate to the treatment ofthe abnormal pathological movements of Huntington's disease.

By dyskinesias caused by a chemical treatment is meant within themeaning of the invention dyskinesias which appear after administrationof a chemical substance, which is at the origin of this dyskinesia(iatrogenic effect). In this case the dyskinesia caused by said chemicaltreatment is either a main pathology, or a side-effect of this chemicaltreatment. It should be noted that the dyskinesia caused following achemical treatment, can appear during the administration of the compoundor after stopping the treatment. A distinction can be made betweenmid-dose dyskinesias, or also those at the start or end of the dose.

A second subject of the invention is a combination of a compound ofgeneral formula (I) or a salt of general formula (I) defined above withone or more other chemical compounds, having or not having a therapeuticeffect, in particular with a compound having a psychotropic effect.

Preferably, the combination according to the invention is a compound ofgeneral formula (I) or a salt of general formula (I) defined above andat least one compound chosen from the dopamine agonists, MAO inhibitors,catecholamine O-methyltransferase inhibitors or neuroleptics.

Among the dopamine agonists, there can be mentioned inter aliapergolide, bromocriptine or carbergoline, ropinirole or pramipexole.

More preferentially, the compound according to the invention of generalformula (I) defined above or its salt can be used in combination withmethyldopa or also L-Dopa.

Still more preferentially, the combination according to the invention isa compound of general formula (I) defined above or its salt and L-Dopa.

In particular, the invention relates to the combination of4-[2-(aminomethyl)-1,3-thiazol-4-yl]-2,6-di(tert-butyl)phenol or itssalt and L-Dopa.

In particular, the invention relates to the combination of4-{2-[(1R)-1-aminoethyl]-1,3-thiazol-4-yl}-2,6-di-tert-butylphenol orits salt and L-Dopa.

In particular, the invention relates to the combination of4-{2-[(1S)-1-aminoethyl]-1,3-thiazol-4-yl}-2,6-di-tert-butylphenol orits salt and L-Dopa.

The combination according to the invention is preferably a combinedpreparation for simultaneous or separate use or use spread over time inorder to treat or prevent dyskinesias, in particular dyskinesias causedby a chemical treatment, in particular induced or tardive dyskinesias.

According to a variant of the use or of the combination according to theinvention, it is possible to use or combine a decarboxylase inhibitorsuch as benserazide or carbidopa with the invention.

The compound of general formula (I) or its salt used according to theinvention or the combination according to the invention can be in solidform, for example powders, granules, tablets, gelatin capsules,liposomes or suppositories. Appropriate solid supports can be, forexample, calcium phosphate, magnesium stearate, talc, sugars, lactose,dextrin, starch, gelatin, cellulose, methyl cellulose, sodiumcarboxymethyl cellulose, polyvinylpyrrolidine and wax.

The compound of general formula (I) or its salt used according to theinvention or the combination according to the invention can also bepresented in liquid form; for example, solutions, emulsions, suspensionsor syrups. Appropriate liquid supports can be, for example, water,organic solvents such as glycerol or the glycols; similarly theirmixtures, in varying proportions, in water.

The administration of a compound of general formula (I) or its salt usedaccording to the invention or the combination according to the inventioncan be carried out for example by topical, oral, parenteral route, byintramuscular or sub-cutaneous injection. The administration dose can becomprised between 0.01 my and 10 g depending on the type of activeingredient used.

The following examples illustrate the invention without limiting itsscope.

BRIEF DESCRIPTION OF THE SEVERAL VIEWS OF THE DRAWINGS

FIG. 1 represents the effect of the treatment with the compoundsaccording to the invention on rats suffering from induced dyskinesia.

FIG. 2 represents the effect of the treatment with the compoundsaccording to the invention on rats suffering from tardive dyskinesia.

EXAMPLES

The following compounds:

-   -   Compound 1:        4-[2-(aminomethyl)-1,3-thiazol-4-yl]-2,6-di(tert-butyl)phenol        hydrochloride or dihydrochloride;    -   Compound 2:        4-{2-[(1R)-1-aminoethyl]-1,3-thiazol-4-yl}-2,6-di-tert-butylphenol        hydrochloride

were subjected to the test for studying dyskinesias induced by L-DOPA inrats and to the test for studying tardive dyskinesias in rats followinglong-term treatment with a neuroleptic.

The synthesis of these compounds is described in the Application WO01/26656.

Example 1 Study of Dyskinesias Induced by L-DOPA

Principle of the In Vivo Test (Experimental Model with Dyskinetic Rats):

An animal model is produced where the dyskinesia is induced in animalstreated with L-Dopa (3-(3,4-dihydroxyphenyl)-L-alanine). First of all inorder to cause a reduction in the level of endogenous dopamine at thelevel of the striatum, lesions are produced in the rats using6-hydroxydopamine (6-OHDA). Following this injection of 6-OHDA, theseanimals become sensitive to the side-effects of L-dopa. In fact in orderto remedy this endogenous dopamine deficiency, the rats receive anL-Dopa based treatment. However the treatment with L-Dopa causes adyskinesia in the rat resulting from too greater quantities of exogenousL-Dopa which reach the brain and above all because of the lesions to thedopaminergic neurons which no longer regulate the endogenous dopaminelevel. The dyskinesia thus induced is evaluated by a statisticalbehaviour test.

Note: in order to improve the L-Dopa-based treatment, the latter isadministered in combination with a decarboxylase inhibitor such asbenserazide. In fact the L-Dopa passes through the hematoencephalicbarrier with difficulty and therefore it can be decarboxylated at theperipheral level.

Measurement of Dyskinesias:

1/ Selection of Rats:

The study was carried out on young male rats. The rats are anaesthetized(chloral 400 mg/kg). Then they receive 2 stereotaxic injections of 6 μgof 6-hydroxydopamine in the left striatum using a 10 μl Hamiltonmicrosyringe. The rats receive in fine 12 μg of 6-OHDA dissolved in 4 μlof 0.02% L-ascorbate. Four weeks later the lesion to the locus niger isproduced in the rats. In order to quantify this lesion, an indirectmeasurement is used: the rotations induced by apomorphine (substancetest). The animals receive a sub-cutaneous injection of 0.5 mg/kg ofapomorphine and the right and left rotations of the animals are measuredover 30 minutes. A net rotational asymmetry score is then determined.This score is expressed as the number of complete turns in the testcage/minute in the contralateral direction of the lesion.

The rats which exhibit an individual average greater than 4 completeturns/minute in the contralateral direction of the lesion are selectedin order to carry out the in vivo test. This net rotational asymmetryscore corresponds to animals the locus niger of which has significantlesions and which exhibit at least 90% dopamine depletion in thestriatum (Lee et al.; 1996; Lundblad et al., 2002; Winkler et al.,1996).

2/ Induction of Dyskinesia in the Selected Rats:

Six weeks after the 6-hydroxydopamine (6-OHDA) lesions, the selectedrats receive a daily intraperitoneal injection of L-Dopa methylester ata dose of 20 mg/kg and benserazide at a dose of 15 mg/kg. The injectionstake place from week 6 to week 9. From week 10, the rats receive a moreconcentrated dose: each day they receive an intraperitoneal injection ofL-Dopa methylester at a dose of 25 mg/kg and benserazide at a dose of 15mg/kg. From week 11, the rats receive two daily injections of L-Dopamethylester at a dose of 15 mg/kg and benserazide at a dose of 15 mg/kg.During week 11, the rats are evaluated 3 times per week for their levelof abnormal and involuntary movements in order to determine whether theadministered doses are sufficient to cause a dyskinesia in theseanimals. The rats are observed individually from 30 minutes to 180minutes after injection of the L-Dopa; they are observed every 30minutes. The movements which are observed at that time are considered tobe dyskinetic movements when they meet the following criteria:

-   -   the movements are induced by the L-Dopa;    -   the movements affect the side of the body in the contralateral        direction of the lesion;    -   the movements are repetitive, involuntary and cannot be        attributed to normal behaviour.

The abnormal and involuntary movements are classified in 4 sub-types:

-   -   locomotive dyskinesia: increase in locomotion of the side        contralateral to the lesion;    -   axial dystonia: deviation of the posture of the neck and of the        upper part of the body;    -   oromandibular dyskinesia: stereotypical movements of the jaws        and protrusion of the tongue;    -   dyskinesia of the anterior limbs: repetitive and rhythmic        jerking of the anterior limbs accompanied by a dystonic posture        and/or strong grasping movements of the paws.

For each of these sub-types, the rats are marked on a scale of 0 to 4,knowing that:

-   -   0=no movement,    -   1=occasional movements,    -   2=frequent movements,    -   3=continuous movements but interrupted by a sensory distraction,    -   4=continuous, acute movements, not interrupted by a sensory        distraction.

The compounds according to the invention are tested in order todetermine their ability to modulate the effects of the L-Dopa. For thispurpose, the rats which exhibit a sufficient rate of abnormal andinvoluntary movements (rate greater than 2 for one observed movement andtotal rate greater than 8 for the 4 observed movements) are selected andcontinue to receive 2 to 4 injections/week of L-Dopa. After 12 to 14weeks, the oral treatment with the compounds according to the inventionto be tested starts and the rate of abnormal and involuntary movementsis evaluated.

For each animal receiving a compound to be tested, another animalreceives the solvent of the compound to be tested, generally water.

Results:

The rate of abnormal and involuntary movements is calculatedstatistically for each group of rats. The results are presented in FIG.1 for compounds 1 and 2.

Compound 1 according to the invention is administered orally at a doseof 30 mg/kg to dyskinetic rats according to the protocol of Example 1described above. The results presented were obtained with 9 testedanimals.

Compound 2 according to the invention is administered orally at a doseof 10 and 30 mg/kg to dyskinetic rats according to the protocol ofExample 1 described above. The results presented were obtained with 9tested animals.

The score obtained makes it possible to evaluate the dyskinesia of therat. The higher the numerical value of the score, the more dyskineticthe animal, with a maximum of 16 points.

-   -   compound 1: at a dose of 30 mg/kg, the score is reduced from        11.3 to 9.6 after 180 minutes of treatment.        -   At time 120 minutes after the administration of L-Dopa, the            rats treated with compound 1 have a score of 10 points            whilst the control (water) has a score of 12 points;    -   Compound 2: at a dose of 30 mg/kg, the score is reduced from        13.8 to 9 points and at a dose of 10 mg/kg, the score is reduced        from 13 to 10.6 points after 180 minutes of treatment.        -   At time 120 minutes after the administration of L-Dopa, the            rats treated with compound 2 (30 mg/kg) have a score of 9.7            points whereas the control (water) has a score of 12.9.

The results indicate a dose-dependent effectiveness of the treatmentwith Compounds 1 and 2 on the rats suffering from induced dyskinesia.This effectiveness is statistically significant. Compounds 1 and 2 dohave an anti-dyskinetic effect.

Example 2 Study of Tardive Dyskinesia in Rats Treated with a NeurolepticOver a Long Period

Principle of the In Vivo Test (Experimental Model with Rats):

Tardive dyskinesia is a complication resulting from prolonged treatmentwith for example neuroleptics. It is characterized by repetitive,involuntary movements of the mouth, face and tongue. Long-term treatmentwith neuroleptics can lead to oromandibular dyskinesia, in particular itcan lead to movements of mastication and protrusion of the tongue inrats. The principle of the test is to quantify the abnormal movements ofthe animals in a test cage during a determined time window (5 minutes).

Induction of Orofacial Dyskinesia in Rats:

A neuroleptic, haloperidol (originating from Sigma®), is administeredover a long period to rats using an Alzet® osmotic pump. This osmoticpump (reference 2ML4 Alzet®) is filled with a solution of haloperidol at10 mg/ml. This pump is implanted subcutaneously in rats weighing between150 g and 160 g. After anaesthesia of the rats with isoflurane, a smallincision is made in the skin at the level of the scapulae to allowinsertion of the pump. Then the incision is sutured. The pump makes itpossible to continuously administer haloperidol to the rats at a dose of2 mg/kg/day for 28 days.

Measurement of Dyskinesia in Rats:

Between 21 to 28 days after the insertion of the pump, 12 rats arechosen at random for the test. 6 of them are treated with water(control), and the other 6 rats receive the compounds according to theinvention.

Before the treatment (t=0) with the compounds to be tested, the rats areplaced individually in plastic test cages. After a adaptation period of2 minutes in the cage, the number of protrusions of the tongue andmastication movements is counted for 5 minutes. Then the treatment(compounds 1 and 2 to be tested) is administered orally at a dose of 2ml/kg. Then the number of protrusions of the tongue and masticationmovements is counted for 2 periods of 5 minutes each at t=1 hour and att=3 hours after administration of the compound according to theinvention.Results:

The rate of protrusion of the tongue and mastication movements iscalculated statistically for each group of rats. The results arepresented in FIG. 2 a and b for Compound 1 and in FIG. 2 c and d forCompound 2.

Compounds 1 and 2 according to the invention are administered orally ata dose of 10 and 30 mg/kg to dyskinetic rats according to the protocolof Example 2 described above. The results presented were obtained with 8tested animals.

The score obtained makes it possible to evaluate the dyskinesia of therat. The higher the numerical value of the score, the more dyskineticthe animal.

-   -   Compound 1: at a dose of 10 mg/kg, the score of chewing        movements is reduced from 30.3 to 21. At a dose of 30 mg/kg, the        score of chewing movements is reduced from 35.6 to 11.9.    -   Compound 2: at a dose of 10 mg/kg, the rate of protrusion of the        tongue is significantly reduced after 3 hours, from 11.4 to 5.        At a dose of 30 mg/kg, the number of mastication movements and        the rate of protrusion of the tongue is significantly reduced        after 3 hours, from 35.5 to 23.7 and from 15 to 6 respectively.

The results indicate a dose-dependent effectiveness of treatment withCompounds 1 and 2 on rats suffering from tardive dyskinesia and tardiveorofacial dyskinesia caused by haloperidol. Compounds 1 and 2 do have ananti-dyskinetic effect.

The invention claimed is:
 1. A method for treating a dyskinesia causedby a chemical treatment comprising administering to a patient in needthereof a compound of general formula (I)

wherein: A represents (A1)

wherein R⁵ represents hydrogen or alkyl, R⁶, R⁷, and R⁸ representindependently hydrogen, alkyl, cycloalkyl, hydroxy, or alkoxy; Brepresents hydrogen or alkyl; n represents an integer from 0 to 5; R¹and R² represent independently hydrogen, alkyl, or cycloalkyl; R³ and R⁴represent independently hydrogen, alkyl or R³ and R⁴ form together withthe nitrogen atom to which they are attached a heterocycle comprising 1to 2 heteroatoms and 5 to 7 members, wherein the members of theheterocycle include —CH₂—, —NR¹⁴—, —O— or —S—, R¹⁴ representing ahydrogen, alkyl, —COR¹⁵, —COOR¹⁵, or —CONR¹⁶R¹⁷, R¹⁵ representing alkyland R¹⁶ and R¹⁷ represent independently hydrogen or alkyl; or of a saltof general formula (I) defined above, wherein the compound of generalformula (I) is the only active ingredient for treating the dyskinesia.2. The method of claim 1, wherein R⁵ is hydrogen.
 3. The method of claim1, wherein R⁶, R⁷, and R⁸ represent independently hydrogen or alkyl. 4.The method of claim 1, wherein n is between 0 and
 3. 5. The method ofclaim 1, wherein n is equal to
 0. 6. The method of claim 1, wherein R¹represents hydrogen.
 7. The method of claim 1, wherein R² representshydrogen or alkyl.
 8. The method of claim 1, wherein R³ or R⁴ representshydrogen or alkyl.
 9. The method of claim 1, wherein the method treatsinduced dyskinesia or tardive dyskinesia.
 10. The method of claim 1,wherein the method treats a dyskinesia caused by levodopa (L-Dopa),levodopa-benzerazide combination, levodopa-carbodopa combination,pergolide, quinpirole, carbergoline, benzotropine, trihexylphenidyl,ropinirole, or pramipexole.
 11. The method of claim 1, wherein thecompound is:4-[2-(aminomethyl)-1,3-thizol-4-yl]-2,6-di(tert-butyl)phenyl;4-{2-[(1R)-1-aminoethyl]-1,3-thiazol-4-yl}-2,6-di-tert-butylphenol; or4-{2-[(1S)-1-aminoethyl]-1,3-thiazol-4-yl}-2,6-di-tert-butylphenol.